Long QT syndrome
Encyclopedia
The long QT syndrome is a rare inborn heart condition in which delayed repolarization
of the heart following a heartbeat increases the risk of episodes of torsade de pointes (TDP, a form of irregular heartbeat that originates from the ventricles
). These episodes may lead to palpitation
s, fainting
and sudden death
due to ventricular fibrillation
. Episodes may be provoked by various stimuli, depending on the subtype of the condition.
The condition is so named because of the appearances of the electrocardiogram
(ECG/EKG), on which there is prolongation of the QT interval
. In some individuals the QT prolongation occurs only after the administration of certain medications.
(APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype
, with some variants having associated syndactyly
(LQT8) or congenital neural deafness (LQT1). A number of specific gene loci have been identified that are associated with LQTS. Genetic testing for LQTS is clinically available and may help to direct appropriate therapies (Overview of LQTS Genetic Testing). The most common causes of LQTS are mutations in the genes KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3); the following is a list of all known genes associated with LQTS:
Drug induced LQT is usually a result of treatment by anti-arrhythmic
drugs such as amiodarone
and sotalol
or a number of other drugs that have been reported to cause this problem (e.g. cisapride
). Some anti-psychotic drugs, such as haloperidol
and ziprasidone
, have a prolonged QT interval as a rare side-effect. Genetic mutations may make one more susceptible to drug-induced LQT.
LQT1
LQT1 is the most common type of long QT syndrome, making up about 30 to 35 percent of all cases. The LQT1 gene
is , which has been isolated to chromosome
11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1
that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (in particular, the minK beta subunit) to create the IKs ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential
.
Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene, homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome
.
Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine
. This can also unmark latent carriers of the LQT1 gene.
Many missense mutation
s of the LQT1 gene have been identified. These are often associated with a high frequency of syncopes but less sudden death than LQT2.
LQT2
The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 25 to 30 percent of all cases. This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (hERG
) on chromosome 7. The hERG
gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential
, and therefore the length of the QT interval.) The normally functioning hERG
gene allows protection against early after depolarizations (EADs).
Most drugs that cause long QT syndrome do so by blocking the IKr current via the hERG
gene. These include erythromycin
, terfenadine
, and ketoconazole
. The hERG channel is very sensitive to unintended drug binding due to two aromatic amino acid
s, the tyrosine
at position 652 and the phenylalanine
at position 656. These amino acid residues are poised so that a drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are, therefore, not as prone to blockage.
LQT3
The LQT3 type of long QT syndrome involves mutation of the gene that encodes the alpha subunit of the Na+
ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A
(also hH1 and NaV1.5). The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. However, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.
A large number of mutations have been characterized as leading to or predisposing to LQT3. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore, mutations in SCN5A
can cause Brugada syndrome
, cardiac conduction disease and dilated cardiomyopathy
. In rare situations, some affected individuals can have combinations of these diseases.
LQT5
is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1, which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms, it can lead to Jervell and Lange-Nielsen syndrome
LQT6
is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2, which encodes for the potassium channel beta subunit MiRP1, constituting part of the IKr repolarizing K+ current.
LQT7
Andersen-Tawil syndrome
is an autosomal dominant form of LQTS associated with skeletal deformities. It involves mutation in the gene KCNJ2, which encodes for the potassium channel protein Kir 2.1. The syndrome is characterized by Long QT syndrome with ventricular arrhythmias, periodic paralysis, and skeletal developmental abnormalities as clinodactyly, low-set ears and micrognathia. The manifestations are highly variable.
LQT8
Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly, and immune deficiency.
LQT9
This newly discovered variant is caused by mutations in the membrane structural protein, caveolin
-3 . Caveolins form specific membrane domains called caveolae
in which among others the NaV1.5 voltage-gated sodium channel sits. Similar to LQT3, these particular mutations increase so-called 'late' sodium current, which impairs cellular repolarization
.
LQT10
This novel susceptibility gene for LQT is SCN4B encoding the protein NaVβ4, an auxiliary subunit
to the pore-forming NaV1.5 (gene: SCN5A) subunit of the voltage-gated sodium channel of the heart. The mutation leads to a positive shift in inactivation of the sodium current, thus increasing sodium current. Only one mutation in one patient has so far been found.
(JLNS) is an autosomal recessive form of LQTS with associated congenital deafness. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes
In untreated individuals with JLNS, about 50 percent die by the age of 15 years due to ventricular arrhythmias.
is an autosomal dominant form of LQTS that is not associated with deafness. The diagnosis is clinical and is now less commonly used in centres where genetic testing is available, in favour of the LQT1 to 10 scheme given above.
s. After-depolarizations (which occur more commonly in LQTS) can be propagated to neighboring cells due to the differences in the refractory periods, leading to re-entrant ventricular arrhythmias.
It is believed that the so-called early after-depolarizations (EADs) that are seen in LQTS are due to re-opening of L-type calcium channel
s during the plateau phase of the cardiac action potential
. Since adrenergic
stimulation can increase the activity of these channels, this is an explanation for why the risk of sudden death in individuals with LQTS is increased during increased adrenergic states (i.e., exercise, excitement) -- especially since repolarization is impaired. Normally during adrenergic states, repolarizing currents will also be enhanced to shorten the action potential. In the absence of this shortening and the presence of increased L-type calcium current, EADs may arise.
The so-called delayed after-depolarizations (DADs) are thought to be due to an increased Ca2+ filling of the sarcoplasmic reticulum. This overload may cause spontaneous Ca2+ release during repolarization, causing the released Ca2+ to exit the cell through the 3Na+/Ca2+-exchanger, which results in a net depolarizing current.
In 2004, it was shown that genotype and QT interval duration are independent predictors of recurrence of life-threatening events during beta-blockers therapy. To be specific, the presence of QTc >500ms and LQT2 and LQT3 genotype are associated with the highest incidence of recurrence. In these patients, primary prevention with ICD
(Implantable cardioverter-defibrillator) implantation can be considered.
(ICD). Also, external defibrillation can be used to restore sinus rhythm. ICDs are commonly used in patients with syncope
s despite beta blocker therapy, and in patients having experienced a cardiac arrest.
It is hoped that, with better knowledge of the genetics underlying the long QT syndrome, more precise treatments will become available.
QTc>500 msec LQT1 & LQT2 & LQT3 (males)
QTc>500 msec LQT3 (females)
QTc<500 msec LQT2 (females) & LQT3
QTc<500 msec LQT1 & LQT2 (males)
by Meissner in 1856, where a deaf girl died after her teacher yelled at her. When the parents were told about her death, they told that her older brother who also was deaf died after a terrible fright. This was several decades before the ECG was invented, but is likely the first described case of Jervell and Lange-Nielsen syndrome
. In 1957, the first case documented by ECG was described by Anton Jervell and Fred Lange-Nielsen, working in Tønsberg
, Norway
. Italian pediatrician Cesarino Romano, in 1963, and Irish pediatrician Owen Conor Ward, in 1964, separately described the more common variant of Long QT syndrome with normal hearing, later called Romano-Ward syndrome. The establishment of the International Long-QT Syndrome Registry in 1979 allowed numerous pedigrees
to be evaluated in a comprehensive manner. This helped in detecting many of the numerous genes involved.
Repolarization
In neuroscience, repolarization refers to the change in membrane potential that returns the membrane potential to a negative value after the depolarization phase of an action potential has just previously changed the membrane potential to a positive value. Repolarization results from the movement...
of the heart following a heartbeat increases the risk of episodes of torsade de pointes (TDP, a form of irregular heartbeat that originates from the ventricles
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
). These episodes may lead to palpitation
Palpitation
A palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself...
s, fainting
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
and sudden death
Sudden Cardiac Death
Sudden cardiac death is natural death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms. Other forms of sudden death may be noncardiac in origin...
due to ventricular fibrillation
Ventricular fibrillation
Ventricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...
. Episodes may be provoked by various stimuli, depending on the subtype of the condition.
The condition is so named because of the appearances of the electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
(ECG/EKG), on which there is prolongation of the QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
. In some individuals the QT prolongation occurs only after the administration of certain medications.
Genes and mutations
LQTS can arise from mutation of one of several genes. These mutations tend to prolong the duration of the ventricular action potentialVentricular action potential
In electrocardiography, the ventricular myocyte membrane potential is about -90 mV at rest, which is close to the potassium reversal potential. When an action potential is generated, the membrane potential rises above this level in four distinct phases....
(APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
, with some variants having associated syndactyly
Syndactyly
Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and kangaroo, but is an unusual condition in humans.-Classification:...
(LQT8) or congenital neural deafness (LQT1). A number of specific gene loci have been identified that are associated with LQTS. Genetic testing for LQTS is clinically available and may help to direct appropriate therapies (Overview of LQTS Genetic Testing). The most common causes of LQTS are mutations in the genes KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3); the following is a list of all known genes associated with LQTS:
| Type | OMIM | Mutation | Notes >- | LQT1 |
alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 KvLQT1 Kv7.1 is a potassium channel protein coded for by the gene KCNQ1. Kv7.1 is present in the cell membranes of cardiac muscle tissue and in inner ear neurons among other tissues... or KCNQ1) |
minK Mink There are two living species referred to as "mink": the European Mink and the American Mink. The extinct Sea Mink is related to the American Mink, but was much larger. All three species are dark-colored, semi-aquatic, carnivorous mammals of the family Mustelidae, which also includes the weasels and... ) is known as IKs. These mutations often cause LQT by reducing the amount of repolarizing current. This repolarizing current is required to terminate the action potential, leading to an increase in the action potential duration (APD). These mutations tend to be the most common yet least severe. >- | LQT2 |
alpha subunit of the rapid delayed rectifier potassium channel (hERG HERG hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel... + MiRP1) |
Kr. This phenotype is also probably caused by a reduction in repolarizing current. >- | LQT3 |
alpha subunit of the sodium channel (SCN5A SCN5A The Nav1.5 is a sodium ion channel protein that in humans is encoded by the SCN5A gene. Mutations in the gene are associated with long QT syndrome type 3 , Brugada syndrome, primary cardiac conduction disease and idiopathic ventricular fibrillation.... ) |
Na. Depolarizing current through the channel late in the action potential is thought to prolong APD. The late current is due to the failure of the channel to remain inactivated. As a consequence, it can enter a bursting mode, during which significant current enters abruptly when it should not. These mutations are more lethal but less common. >- | LQT4 |
anchor protein Ankyrin B | >- | beta subunit MinK (or KCNE1 KCNE1 Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.KCNE1 is a gene associated with Long QT syndrome type 5. It can both cause Romano-Wards syndrome and Jervell Lange-Nielsens syndrome -External links:*... ), which coassembles with KvLQT1 KvLQT1 Kv7.1 is a potassium channel protein coded for by the gene KCNQ1. Kv7.1 is present in the cell membranes of cardiac muscle tissue and in inner ear neurons among other tissues... |
>- | beta subunit MiRP1 (or KCNE2 KCNE2 Potassium voltage-gated channel subfamily E member 2 is a protein that in humans is encoded by the KCNE2 gene. The protein encoded by this gene is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome.... ), which coassembles with hERG HERG hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel... |
>- | potassium channel KCNJ2 KCNJ2 The Kir2.1 inward-rectifier potassium ion channel is encoded by the gene.- Clinical significance :A defect in this gene is associated with Andersen-Tawil syndrome.A mutation in the KCNJ2 gene has also been shown to cause short QT syndrome.... (or Kir2.1) |
ir2.2) is called IK1. LQT7 leads to Andersen-Tawil syndrome Andersen-Tawil syndrome Andersen–Tawil syndrome, also called Andersen syndrome and Long QT syndrome 7, is a form of long QT syndrome. It is a rare genetic disorder, and is inherited in an autosomal dominant pattern.- Presentation :... . >- | LQT8 |
alpha subunit of the calcium channel Calcium channel A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:... Cav1.2 encoded by the gene CACNA1c CACNA1C Calcium channel, voltage-dependent, L type, alpha 1C subunit is a protein that in humans is encoded by the CACNA1C gene. Cav1.2 is a subunit of L-type voltage-dependent calcium channel.- Structure and function :... . |
Leads to Timothy's syndrome. |
| Caveolin 3 Caveolin 3 Caveolin-3 is a protein that in humans is encoded by the CAV3 gene.-Interactions:Caveolin 3 has been shown to interact with Epidermal growth factor receptor, Dysferlin and Dystroglycan.-Further reading:... |
|||
| SCN4B SCN4B Sodium channel, also known as SCN4B is a protein which in humans is encoded by the SCN4B gene.SCN4B is a sodium channel associated with long QT syndrome.-External links:*... |
|||
| LQT11 | AKAP9 AKAP9 A-kinase anchor protein 9 is an enzyme that in humans is encoded by the AKAP9 gene.-Interactions:AKAP9 has been shown to interact with Calmodulin 1, FNBP1, CALM2, Protein kinase N1, TRIP10, KvLQT1 and PRKAR2A.-Further reading:... |
||
| LQT12 | SNTA1 SNTA1 Alpha-1-syntrophin is a protein that in humans is encoded by the SNTA1 gene.-Interactions:Syntrophin, alpha 1 has been shown to interact with Dystrophin, Nav1.1 and Nav1.5.-Further reading:... |
||
| LQT13 | GIRK4 |
Drug induced LQT is usually a result of treatment by anti-arrhythmic
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....
drugs such as amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
and sotalol
Sotalol
Sotalol is a drug used in individuals with rhythm disturbances of the heart, and to treat hypertension in some individuals. It is a non-selective competitive β-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels...
or a number of other drugs that have been reported to cause this problem (e.g. cisapride
Cisapride
Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
). Some anti-psychotic drugs, such as haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
and ziprasidone
Ziprasidone
Ziprasidone was the fifth atypical antipsychotic to gain FDA approval . In the United States, Ziprasidone is Food and Drug Administration approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients...
, have a prolonged QT interval as a rare side-effect. Genetic mutations may make one more susceptible to drug-induced LQT.
LQT1
LQT1 is the most common type of long QT syndrome, making up about 30 to 35 percent of all cases. The LQT1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is , which has been isolated to chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1
KvLQT1
Kv7.1 is a potassium channel protein coded for by the gene KCNQ1. Kv7.1 is present in the cell membranes of cardiac muscle tissue and in inner ear neurons among other tissues...
that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (in particular, the minK beta subunit) to create the IKs ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential
Cardiac action potential
In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
.
Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene, homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome, a type of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. If untreated, the irregular heartbeats, called arrhythmias, can lead to fainting, seizures, or sudden death...
.
Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
. This can also unmark latent carriers of the LQT1 gene.
Many missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
s of the LQT1 gene have been identified. These are often associated with a high frequency of syncopes but less sudden death than LQT2.
LQT2
The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 25 to 30 percent of all cases. This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (hERG
HERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
) on chromosome 7. The hERG
HERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential
Cardiac action potential
In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
, and therefore the length of the QT interval.) The normally functioning hERG
HERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
gene allows protection against early after depolarizations (EADs).
Most drugs that cause long QT syndrome do so by blocking the IKr current via the hERG
HERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
gene. These include erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, terfenadine
Terfenadine
Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel and marketed under various brand names including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia...
, and ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
. The hERG channel is very sensitive to unintended drug binding due to two aromatic amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, the tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
at position 652 and the phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
at position 656. These amino acid residues are poised so that a drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are, therefore, not as prone to blockage.
LQT3
The LQT3 type of long QT syndrome involves mutation of the gene that encodes the alpha subunit of the Na+
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A
SCN5A
The Nav1.5 is a sodium ion channel protein that in humans is encoded by the SCN5A gene. Mutations in the gene are associated with long QT syndrome type 3 , Brugada syndrome, primary cardiac conduction disease and idiopathic ventricular fibrillation....
(also hH1 and NaV1.5). The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. However, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.
A large number of mutations have been characterized as leading to or predisposing to LQT3. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore, mutations in SCN5A
SCN5A
The Nav1.5 is a sodium ion channel protein that in humans is encoded by the SCN5A gene. Mutations in the gene are associated with long QT syndrome type 3 , Brugada syndrome, primary cardiac conduction disease and idiopathic ventricular fibrillation....
can cause Brugada syndrome
Brugada syndrome
The Brugada syndrome is a genetic disease that is characterised by abnormal electrocardiogram findings and an increased risk of sudden cardiac death. It is named by the Spanish cardiologists Pedro Brugada and Josep Brugada...
, cardiac conduction disease and dilated cardiomyopathy
Dilated cardiomyopathy
Dilated cardiomyopathy or DCM is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently. The decreased heart function can affect the lungs, liver, and other body systems....
. In rare situations, some affected individuals can have combinations of these diseases.
LQT5
is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1, which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms, it can lead to Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome, a type of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. If untreated, the irregular heartbeats, called arrhythmias, can lead to fainting, seizures, or sudden death...
LQT6
is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2, which encodes for the potassium channel beta subunit MiRP1, constituting part of the IKr repolarizing K+ current.
LQT7
Andersen-Tawil syndrome
Andersen-Tawil syndrome
Andersen–Tawil syndrome, also called Andersen syndrome and Long QT syndrome 7, is a form of long QT syndrome. It is a rare genetic disorder, and is inherited in an autosomal dominant pattern.- Presentation :...
is an autosomal dominant form of LQTS associated with skeletal deformities. It involves mutation in the gene KCNJ2, which encodes for the potassium channel protein Kir 2.1. The syndrome is characterized by Long QT syndrome with ventricular arrhythmias, periodic paralysis, and skeletal developmental abnormalities as clinodactyly, low-set ears and micrognathia. The manifestations are highly variable.
LQT8
Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly, and immune deficiency.
LQT9
This newly discovered variant is caused by mutations in the membrane structural protein, caveolin
Caveolin
Caveolins are a family of integral membrane proteins which are the principal components of caveolae membranes and involved in receptor-independent endocytosis. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules...
Caveolae
In biology, caveolae , which are a special type of lipid raft, are small invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes....
in which among others the NaV1.5 voltage-gated sodium channel sits. Similar to LQT3, these particular mutations increase so-called 'late' sodium current, which impairs cellular repolarization
Repolarization
In neuroscience, repolarization refers to the change in membrane potential that returns the membrane potential to a negative value after the depolarization phase of an action potential has just previously changed the membrane potential to a positive value. Repolarization results from the movement...
.
LQT10
This novel susceptibility gene for LQT is SCN4B encoding the protein NaVβ4, an auxiliary subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
to the pore-forming NaV1.5 (gene: SCN5A) subunit of the voltage-gated sodium channel of the heart. The mutation leads to a positive shift in inactivation of the sodium current, thus increasing sodium current. Only one mutation in one patient has so far been found.
Jervell and Lange-Nielsen syndrome
The Jervell and Lange-Nielsen syndromeJervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome, a type of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. If untreated, the irregular heartbeats, called arrhythmias, can lead to fainting, seizures, or sudden death...
(JLNS) is an autosomal recessive form of LQTS with associated congenital deafness. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes
In untreated individuals with JLNS, about 50 percent die by the age of 15 years due to ventricular arrhythmias.
Romano-Ward syndrome
Romano-Ward syndromeRomano-Ward syndrome
Romano-Ward syndrome, is the major variant of long QT syndrome. It is a condition that causes a disruption of the heart's normal rhythm. This disorder is a form of long QT syndrome, which is a heart condition that causes the cardiac muscle to take longer than usual to recharge between beats...
is an autosomal dominant form of LQTS that is not associated with deafness. The diagnosis is clinical and is now less commonly used in centres where genetic testing is available, in favour of the LQT1 to 10 scheme given above.
Pathophysiology
All forms of the long QT syndrome involve an abnormal repolarization of the heart. The abnormal repolarization causes differences in the refractory period of the myocyteMyocyte
A myocyte is the type of cell found in muscles. They arise from myoblasts.Each myocyte contains myofibrils, which are long, long chains of sarcomeres, the contractile units of the cell....
s. After-depolarizations (which occur more commonly in LQTS) can be propagated to neighboring cells due to the differences in the refractory periods, leading to re-entrant ventricular arrhythmias.
It is believed that the so-called early after-depolarizations (EADs) that are seen in LQTS are due to re-opening of L-type calcium channel
L-type calcium channel
The L-type calcium channel is a type of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
s during the plateau phase of the cardiac action potential
Cardiac action potential
In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
. Since adrenergic
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
stimulation can increase the activity of these channels, this is an explanation for why the risk of sudden death in individuals with LQTS is increased during increased adrenergic states (i.e., exercise, excitement) -- especially since repolarization is impaired. Normally during adrenergic states, repolarizing currents will also be enhanced to shorten the action potential. In the absence of this shortening and the presence of increased L-type calcium current, EADs may arise.
The so-called delayed after-depolarizations (DADs) are thought to be due to an increased Ca2+ filling of the sarcoplasmic reticulum. This overload may cause spontaneous Ca2+ release during repolarization, causing the released Ca2+ to exit the cell through the 3Na+/Ca2+-exchanger, which results in a net depolarizing current.
Diagnosis
The diagnosis of LQTS is not easy since 2.5% of the healthy population have prolonged QT interval, and 10–15% of LQTS patients have a normal QT interval. A commonly used criterion to diagnose LQTS is the LQTS "diagnostic score". The score is calculated by assigning different points to various criteria (listed below). With four or more points, the probability is high for LQTS; with one point or less, the probability is low. A score of two or three points indicates intermediate probability.- QTc (Defined as QT interval / square root of RR interval)
- >= 480 msec - 3 points
- 460-470 msec - 2 points
- 450 msec and male gender - 1 point
- Torsades de pointesTorsades de pointesTorsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
ventricular tachycardiaVentricular tachycardiaVentricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
- 2 points - T wave alternansT wave alternansT wave alternans is a periodic beat-to-beat variation in the amplitude or shape of the T wave in an electrocardiogram .TWA was first described in 1908. At that time, only large variations could be detected...
- 1 point - Notched T wave in at least 3 leads - 1 point
- Low heart rate for age (children) - 0.5 points
- Syncope (one cannot receive points both for syncope and torsades de pointes)
- With stress - 2 points
- Without stress - 1 point
- Congenital deafness - 0.5 points
- Family history (the same family member cannot be counted for LQTS and sudden death)
- Other family members with definite LQTS - 1 point
- Sudden death in immediate family (members before the age 30) - 0.5 points
Treatment options
Those diagnosed with long QT syndrome are usually advised to avoid drugs that would prolong the QT interval further or lower the threshold for TDP. In addition to this, there are two intervention options for individuals with LQTS: arrhythmia prevention and arrhythmia termination.Arrhythmia prevention
Arrhythmia suppression involves the use of medications or surgical procedures that attack the underlying cause of the arrhythmias associated with LQTS. Since the cause of arrhythmias in LQTS is after depolarizations, and these after depolarizations are increased in states of adrenergic stimulation, steps can be taken to blunt adrenergic stimulation in these individuals. These include:- Administration of beta receptor blocking agentsBeta blockerBeta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
, which decreases the risk of stress-induced arrhythmias. Beta blockers are the first choice in treating Long QT syndrome.
In 2004, it was shown that genotype and QT interval duration are independent predictors of recurrence of life-threatening events during beta-blockers therapy. To be specific, the presence of QTc >500ms and LQT2 and LQT3 genotype are associated with the highest incidence of recurrence. In these patients, primary prevention with ICD
Implantable cardioverter-defibrillator
An implantable cardioverter-defibrillator is a small battery-powered electrical impulse generator which is implanted in patients who are at risk of sudden cardiac death due to ventricular fibrillation and ventricular tachycardia. The device is programmed to detect cardiac arrhythmia and correct it...
(Implantable cardioverter-defibrillator) implantation can be considered.
- Potassium supplementation: If the potassium content in the blood rises, the action potential shortens, and due to this reason it is believed that increasing potassium concentration could minimize the occurrence of arrhythmias. It should work best in LQT2, since the HERG channel is especially sensitive to potassium concentration, but the use is experimental and not evidence-based.
- MexiletineMexiletineMexiletine belongs to the Class IB anti-arrhythmic group of medicines. It is used to treat arrhythmias within the heart, or seriously irregular heartbeats. It slows conduction in the heart and makes the heart tissue less sensitive. Dizziness, heartburn, nausea, nervousness, trembling, unsteadiness...
, a sodium channel blocker: In LQT3, the problem is that the sodium channel does not close properly. Mexiletine closes these channels and is believed to be usable when other therapies fail. It should be especially effective in LQT3, but there is no evidence based documentation. - Amputation of the cervical sympathetic chain (left stellectomyStellate ganglionThe stellate ganglion is a sympathetic ganglion formed by the fusion of the inferior cervical ganglion and the first thoracic ganglion...
). This may be used as an add-on therapy to beta blockers, but modern therapy favors mostly ICD implantation if beta blocker therapy fails.
Arrhythmia termination
Arrhythmia termination involves stopping a life-threatening arrhythmia once it has already occurred. One effective form of arrhythmia termination in individuals with LQTS is placement of an implantable cardioverter-defibrillatorImplantable cardioverter-defibrillator
An implantable cardioverter-defibrillator is a small battery-powered electrical impulse generator which is implanted in patients who are at risk of sudden cardiac death due to ventricular fibrillation and ventricular tachycardia. The device is programmed to detect cardiac arrhythmia and correct it...
(ICD). Also, external defibrillation can be used to restore sinus rhythm. ICDs are commonly used in patients with syncope
Syncope
In phonology, syncope is the loss of one or more sounds from the interior of a word; especially, the loss of an unstressed vowel. It is found bothin Synchronic analysis of languages and Diachronics .-Found synchronically:...
s despite beta blocker therapy, and in patients having experienced a cardiac arrest.
It is hoped that, with better knowledge of the genetics underlying the long QT syndrome, more precise treatments will become available.
Prognosis
The risk for untreated LQTS patients having events (syncopes or cardiac arrest) can be predicted from their genotype (LQT1-8), gender, and corrected QT interval.- High risk (>50%)
QTc>500 msec LQT1 & LQT2 & LQT3 (males)
- Intermediate risk (30-50%)
QTc>500 msec LQT3 (females)
QTc<500 msec LQT2 (females) & LQT3
- Low risk (<30%)
QTc<500 msec LQT1 & LQT2 (males)
History
The first documented case of Long QT syndrome was described in LeipzigLeipzig
Leipzig Leipzig has always been a trade city, situated during the time of the Holy Roman Empire at the intersection of the Via Regia and Via Imperii, two important trade routes. At one time, Leipzig was one of the major European centres of learning and culture in fields such as music and publishing...
by Meissner in 1856, where a deaf girl died after her teacher yelled at her. When the parents were told about her death, they told that her older brother who also was deaf died after a terrible fright. This was several decades before the ECG was invented, but is likely the first described case of Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome, a type of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. If untreated, the irregular heartbeats, called arrhythmias, can lead to fainting, seizures, or sudden death...
. In 1957, the first case documented by ECG was described by Anton Jervell and Fred Lange-Nielsen, working in Tønsberg
Tønsberg
is a city and municipality in Vestfold county, southern Norway, located around north-east of Sandefjord. The administrative centre of the municipality is the city of Tønsberg....
, Norway
Norway
Norway , officially the Kingdom of Norway, is a Nordic unitary constitutional monarchy whose territory comprises the western portion of the Scandinavian Peninsula, Jan Mayen, and the Arctic archipelago of Svalbard and Bouvet Island. Norway has a total area of and a population of about 4.9 million...
. Italian pediatrician Cesarino Romano, in 1963, and Irish pediatrician Owen Conor Ward, in 1964, separately described the more common variant of Long QT syndrome with normal hearing, later called Romano-Ward syndrome. The establishment of the International Long-QT Syndrome Registry in 1979 allowed numerous pedigrees
Pedigree chart
A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next, most commonly humans, show dogs, and race horses....
to be evaluated in a comprehensive manner. This helped in detecting many of the numerous genes involved.
See also
- Cardiac action potentialCardiac action potentialIn electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
- Short QT syndromeShort QT syndromeShort QT syndrome is a genetic disease of the electrical system of the heart. It consists of a constellation of signs and symptoms, consisting of a short QT interval on an EKG that does not significantly change with heart rate, tall and peaked T waves, and a structurally normal heart...
- Steve KonowalchukSteve KonowalchukSteven Reed Konowalchuk is an American former professional ice hockey left winger who played in the NHL with the Washington Capitals and the Colorado Avalanche. He is currently the head coach for the Seattle Thunderbirds of the Western Hockey League...
, a former hockey player who retired after being diagnosed with Long QT syndrome